Some recent philosophical discussions consider whether the brain is best understood as an open or closed system. This issue has major epistemic consequences akin to the scepticism engendered by the famous Cartesian demon. Specifically, one and the same empirical theory of brain function, predictive coding, entailing a prediction model of brain, have been associated with contradictory views of the brain as either open (Clark, 2012, 2013) or closed (Hohwy, 2013, 2014). Based on recent empirical evidence, the present paper argues that contrary to appearances, these views of the brain are compatible with one another. I suggest that there are two main forms of neural activity in the brain, one of which can be characterized as open, and the other as closed. Stimulus-induced activity, because it relies on predictive coding is indeed closed to the world, which entails that in certain respects, the brain is an inferentially secluded and self-evidencing system. In contrast, the brain’s resting state or spontaneous activity is best taken as open because it is a world-evidencing system that allows for the brain’s neural activity to align with the statistically-based spatiotemporal structure of objects and events in the world. This model requires an important caveat, however. Due to its statistically-based nature, the resting state’s alignment to the world comes in degrees. In extreme cases, the degree of alignment can be extremely low, resulting in a resting state that is barely if at all aligned to the world. This is for instance the case in schizophrenia. Clinical symptoms such as delusions and hallucinations in schizophrenics are indicative of the fundamental delicateness of the alignment between the brain’s resting-state and the world’s phenomena. Nevertheless, I argue that so long as we are dealing with a well-functioning brain, the more dire epistemic implications of predictive coding can be forestalled. That the brain is in part a self-evidencing system does not yield any generalizable reason to worry that human cognition is out of step with the real world. Instead, the brain is aligned to the world accounting for “world-brain relation” that mitigates sceptistic worries.